Selection of H3 avian influenza viruses with SAα2,6Gal receptor specificity in pigs

AbstractAvian influenza viruses possess hemagglutinin (HA) which preferentially bind to the sialic acid α2,3-galactose sialyloligosaccharides (SAα2,3Gal) receptor. In contrast, human influenza viruses bind to sialic acid α2,6-galactose sialyloligosaccharides (SAα2,6Gal). The A/Hong Kong/68 (H3N2) virus preferentially binds to SAα2,6Gal, although its HA gene was derived from an avian influenza virus strain. To elucidate the mechanisms behind acquisition of binding specificity for the human-type receptor, the avian influenza virus, A/duck/Hokkaido/5/77 (H3N2), which carries the HA with SAα2,3Gal receptor specificity, was consecutively passaged in pigs. Viruses that preferentially bind to the SAα2,6Gal receptor were predominantly recovered from the nasal swabs of pigs after three passages. The present results indicate that avian influenza viruses can acquire the potential to infect humans after multiple infections in a pig population. Intensive surveillance of swine influenza is, thus, important for the preparedness for the future pandemics

Low replicative fitness of neuraminidase inhibitor-resistant H7N9 avian influenza a virus with R292K substitution in neuraminidase in cynomolgus macaques compared with I222T substitution.

Human cases of H7N9 influenza A virus infection have been increasing since 2013. The first choice of treatment for influenza is neuraminidase (NA) inhibitors (NAIs), but there is a concern that NAI-resistant viruses are selected in the presence of NAIs. In our previous study, an H7N9 virus carrying AA substitution of threonine (T) for isoleucine (I) at residue 222 in NA (NA222T, N2 numbering) and an H7N9 virus carrying AA substitution of lysine (K) for arginine (R) at residue 292 in NA (NA292K, N2 numbering) were found in different macaques that had been infected with A/Anhui/1/2013 (H7N9) and treated with NAIs. In the present study, the variant with NA292K showed not only resistance to NAIs but also lower replication activity in MDCK cells than did the virus with wild-type NA, whereas the variant with NA222T, which was less resistant to NAIs, showed replication activity similar to that of the wild-type virus. Next, we examined the pathogenicity of these H7N9 NAI-resistant viruses in macaques. The variants caused clinical signs similar to those caused by the wild-type virus with similar replication potency. However, the virus with NA292K was replaced within 7 days by that with NA292R (same as the wild-type) in nasal samples from macaques infected with the virus with NA292K, i.e. the so-called revertant (wild-type virus) became dominant in the population in the absence of an NAI. These results suggest that the clinical signs observed in macaques infected with the NA292K virus are caused by the NA292K virus and the NA292R virus and that the virus with NA292K may not replicate continuously in the upper respiratory tract of patients without treatment as effectively as the wild-type virus

Advances in Adjuvanted Influenza Vaccines

The numerous influenza infections that occur every year present a major public health problem. Influenza vaccines are important for the prevention of the disease; however, their effectiveness against infection can be suboptimal. Particularly in the elderly, immune induction can be insufficient, and the vaccine efficacy against infection is usually lower than that in young adults. Vaccine efficacy can be improved by the addition of adjuvants, and an influenza vaccine with an oil-in-water adjuvant MF59, FLUAD, has been recently licensed in the United States and other countries for persons aged 65 years and older. Although the adverse effects of adjuvanted vaccines have been a concern, many adverse effects of currently approved adjuvanted influenza vaccines are mild and acceptable, given the overriding benefits of the vaccine. Since sufficient immunity can be induced with a small amount of vaccine antigen in the presence of an adjuvant, adjuvanted vaccines promote dose sparing and the prompt preparation of vaccines for pandemic influenza. Adjuvants not only enhance the immune response to antigens but can also be effective against antigenically different viruses. In this narrative review, we provide an overview of influenza vaccines, both past and present, before presenting a discussion of adjuvanted influenza vaccines and their future

Inhibition of Eph receptor A4 by 2,5-dimethylpyrrolyl benzoic acid suppresses human pancreatic cancer growing orthotopically in nude mice

Ephrin receptor A4 (EphA4) is overexpressed in human pancreatic adenocarcinoma (PDAC) and activate cell growth. Recent studies have identified small molecules that block EphA4. In this study, we investigated the correlation between EphA4 expression and the prognosis of patients with PDAC. We also examined the cytostatic efficacy of 2,5-dimethylpyrrolyl benzoic acid (compound 1), a small molecule that blocks EphA4, in PDAC cells. Overall survival of patients with EphA4 positivity was significantly shorter than that of patients with EphA4 negativity (P = 0.029). In addition, multivariate analysis revealed that EphA4 expression was an independent prognostic factor in PDAC patients (P = 0.039). Compound 1 showed a cytostatic efficacy in PDAC cells expressing EphA4 in vitro and in vivo. Our study indicated that compound 1 suppressed both EphA4 and Akt phosphorylations, and induced apoptosis in PDAC cells expressing EphA4. In conclusion, compound 1 has a high potential as a therapeutic agent for patients with PDAC

Chemotherapy-Derived Inflammatory Responses Accelerate the Formation of Immunosuppressive Myeloid Cells in the Tissue Microenvironment of Human Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic malignancies. PDAC builds a tumor microenvironment that plays critical roles in tumor progression and metastasis. However, the relationship between chemotherapy and modulation of PDAC-induced tumor microenvironment remains poorly understood. In this study, we report a role of chemotherapy-derived inflammatory response in the enrichment of PDAC microenvironment with immunosuppressive myeloid cells. Granulocyte macrophage colony-stimulating factor (GM-CSF) is a major cytokine associated with oncogenic KRAS in PDAC cells. GM-CSF production was significantly enhanced in various PDAC cell lines or PDAC tumor tissues from patients after treatment with chemotherapy, which induced the differentiation of monocytes into myeloid-derived suppressor cells (MDSC). Furthermore, blockade of GM-CSF with monoclonal antibodies helped to restore T-cell proliferation when cocultured with monocytes stimulated with tumor supernatants. GM-CSF expression was also observed in primary tumors and correlated with poor prognosis in PDAC patients. Together, these results describe a role of GM-CSF in the modification of chemotherapy-treated PDAC microenvironment and suggest that the targeting of GM-CSF may benefit PDAC patients' refractory to current anticancer regimens by defeating MDSC-mediated immune escape.Supplementary data for this article are available at Cancer Research Onlinehttp://cancerres.aacrjournals.org/content/75/13/2629.figures-onl

Reintroduction of H5N1 highly pathogenic avian influenza virus by migratory water birds, causing poultry outbreaks in the 2010-2011 winter season in Japan

H5N1 highly pathogenic avian influenza virus (HPAIV) was reintroduced and caused outbreaks in chickens in 2010-2011 winter season in Japan, which had been free from highly pathogenic avian influenza (HPAI) since 2007 when HPAI outbreaks occurred and were controlled. On October 14, 2010 at Lake Ohnuma, Wakkanai, the northernmost part of Hokkaido, Japan, H5N1 HPAIVs were isolated from fecal samples of ducks flying from their nesting lakes in Siberia. Since then, in Japan, H5N1 HPAIVs have been isolated from 63 wild birds in 17 prefectures and caused HPAI outbreaks in 24 chicken farms in 9 prefectures by the end of March in 2011. Each of these isolates was genetically closely related to the HPAIV isolates at Lake Ohnuma, and those in China, Mongolia, Russia, and Korea, belonging to genetic clade 2.3.2.1. In addition, these isolates were genetically classified into 3 groups, suggesting that the viruses were transmitted by migratory water birds through at least 3 different routes from their northern territory to Japan. These isolates were antigenic variants, which is consistent with selection in poultry under the immunological pressure induced by vaccination. To prevent the perpetuation of viruses in the lakes where water birds nest in summer in Siberia, prompt eradication of HPAIVs in poultry is urgently needed in Asian countries where HPAI has not been controlled

Experimental infection of highly and low pathogenic avian influenza viruses to chicken's, ducks, tree sparrows, jungle crows, and black rats for the evaluation of their roles in virus transmission

Highly pathogenic avian influenza viruses (HPAIVs) have spread in both poultry and wild birds. Determining transmission routes of these viruses during an outbreak is essential for the control of avian influenza. It has been widely postulated that migratory ducks play crucial roles in the widespread dissemination of HPAIVs in poultry by carrying viruses along with their migrations; however close contacts between wild migratory ducks and poultry are less likely in modern industrial poultry farming settings. Therefore, we conducted experimental infections of HPAIVs and low pathogenic avian influenza viruses (LPAIVs) to chickens, domestic ducks, tree sparrows, jungle crows, and black rats to evaluate their roles in virus transmission. The results showed that chickens, ducks, sparrows, and crows were highly susceptible to HPAIV infection. Significant titers of virus were recovered from the sparrows and crows infected with HPAIVs, which suggests that they potentially play roles of transmission of HPAIVs to poultry. In contrast, the growth of LPAIVs was limited in each of the animals tested compared with that of HPAIVs. The present results indicate that these common synanthropes play some roles in influenza virus transmission from wild birds to poultry. (C) 2015 Elsevier B.V. All rights reserved